Shirlene Sampson

Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial

BACKGROUND We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.

Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial

BACKGROUND Electroconvulsive therapy (ECT) is an effective treatment for major depression. Optimising efficacy and minimising cognitive impairment are goals of ongoing technical refinements. AIMS To compare the efficacy and cognitive effects of a novel electrode placement, bifrontal, with two standard electrode placements, bitemporal and right unilateral in ECT. METHOD This multicentre randomised, double-blind, controlled trial (NCT00069407) was carried out from 2001 to 2006. A total of 230 individuals with major depression, bipolar and unipolar, were randomly assigned to one of three electrode placements during a course of ECT: bifrontal at one and a half times seizure threshold, bitemporal at one and a half times seizure threshold and right unilateral at six times seizure threshold. RESULTS All three electrode placements resulted in both clinically and statistically significant antidepressant outcomes. Remission rates were 55% (95% CI 43-66%) with right unilateral, 61% with bifrontal (95% CI 50-71%) and 64% (95% CI 53-75%) with bitemporal. Bitemporal resulted in a more rapid decline in symptom ratings over the early course of treatment. Cognitive data revealed few differences between the electrode placements on a variety of neuropsychological instruments. CONCLUSIONS Each electrode placement is a very effective antidepressant treatment when given with appropriate electrical dosing. Bitemporal leads to more rapid symptom reduction and should be considered the preferred placement for urgent clinical situations. The cognitive profile of bifrontal is not substantially different from that of bitemporal.

Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study

BACKGROUND Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Electroconvulsive therapy is equally effective in unipolar and bipolar depression

Bailine S, Fink M, Knapp R, Petrides G, Husain MM, Rasmussen K, Sampson S, Mueller M, McClintock SM, Tobias KG, Kellner CH. Electroconvulsive therapy is equally effective in unipolar and bipolar depression.

Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study.

OBJECTIVE Depression is often a serious and debilitating illness in adolescents. Unfortunately, a significant number of adolescents do not respond to antidepressant medications or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment intervention shown to benefit depression in adults. This study considered rTMS as an adjunctive treatment in adolescents with major depressive disorder. METHOD This prospective, open, multicenter trial of active adjunctive rTMS was conducted with 8 adolescents with DSM-IV-TR major depressive disorder (MDD) that had not responded sufficiently to 2 adequate antidepressant medication trials. All subjects were maintained on a stable dose of a selective serotonin reuptake inhibitor during the trial. Thirty daily rTMS treatments were given 5 days per week over 6 to 8 weeks. rTMS was applied to the left dorsolateral prefrontal cortex (120% of motor threshold; 10 Hz; 4-second trains; 26-second intertrain interval; 75 trains) for a total of 3,000 stimulations per treatment session. RESULTS Seven of 8 adolescents completed all 30 treatments. rTMS was well tolerated, and no significant safety issues were identified. Suicidal ideation was present at baseline in 3 of the adolescents, and it improved during treatment. The primary outcome measure was the Childrens Depression Rating Scale-Revised (CDRS-R); results improved significantly from baseline (mean [SD]) (65.9 [6.6]) to treatment 10 (50.9 [12]), P < .02. The CDRS-R scores continued to improve through the rTMS treatment series at treatment 20 (40.1 [14]), P < .01; treatment 30 (32.6 [7.3]), P < .0001; and at 6-month follow-up (32.7 [3.8]), P < .0001. CONCLUSIONS This prospective open trial suggests that rTMS is a safe, feasible, and potentially effective adjunctive therapy for treatment-resistant MDD in adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00587639.

Underlying Neurobiology and Clinical Correlates of Mania Status After Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Review of the Literature

Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinsons disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS-induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood-stabilization therapies.

A Randomized Controlled Trial Comparing the Memory Effects of Continuation Electroconvulsive Therapy Versus Continuation Pharmacotherapy: Results From the Consortium for Research in ECT (CORE) Study

OBJECTIVE To compare the memory effects of continuation electroconvulsive therapy (C-ECT) versus continuation pharmacologic intervention (C-PHARM) at 12 and 24 weeks after completion of acute electroconvulsive therapy (ECT). METHOD Eighty-five patients with Structured Clinical Interview for DSM-IV-diagnosed unipolar major depressive disorder, enrolled in a multisite, randomized, parallel-design trial conducted at 5 academic medical centers from 1997 to 2004, who had remitted with an acute course of bilateral ECT and remained unrelapsed through 24 weeks of continuation therapy, were included in this analysis. They were randomly assigned to C-ECT (10 treatments) or nortriptyline plus lithium (monitored by serum blood levels) for 24 weeks. Objective neuropsychological measures of retrograde and anterograde memory and subjective assessment of memory were obtained at baseline, 12 weeks, and 24 weeks. The Rey Auditory-Verbal Learning Test and the Autobiographical Memory Interview were the primary outcome measures. RESULTS The C-PHARM group showed a greater group difference (P < .01) for baseline to 12-week change for the Autobiographical Memory Interview. No other memory measures showed group differences for change scores from baseline to 12 weeks. Groups showed no baseline to 24-week change-score differences on any of the memory measures. For both groups, 12-week objective anterograde memory scores (eg, Auditory-Verbal Learning Test percent retention P = .0001; Rey-Osterrieth Complex Figure or Taylor Figure percent retention P < .002) and 24-week subjective memory scores were significantly improved (Squire Subjective Memory Questionnaire P < .02) over baseline. This result reflects the apparent resolution of a presumed decrement in anterograde memory associated with acute ECT preceding this study. CONCLUSIONS The finding of no memory outcome differences between unrelapsed recipients of C-ECT and C-PHARM is consistent with clinical experience. Memory effects have only a small role in the choice between C-ECT and C-PHARM.

The use of slow-frequency prefrontal repetitive transcranial magnetic stimulation in refractory neuropathic pain

Objective: A number of antidepressant medications, as well as electroconvulsive therapy, have been shown to reduce chronic pain. Slow-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the right dorsolateral prefrontal cortex has also been shown to have an antidepressant effect. Given the high degree of suffering experienced by subjects with chronic neuropathic pain and the treatment resistance noted in this population, the use of slow-frequency rTMS as adjuvant therapy may be of significant clinical benefit. Methods: Fifteen sessions of 1-Hz rTMS (1600 stimulations/session) were applied to the right dorsolateral prefrontal cortex as adjuvant treatment in 9 subjects with refractory neuropathic pain over 3 weeks. Pain and depression ratings were performed at baseline, weekly during rTMS treatment, and monthly for up to 3 months after treatment. Results: Five males and 4 females participated, and all had longstanding refractory neuropathic pain (range, 1-19 years), with an average baseline pain rating of 7.3 and no depression (Hamilton Rating Scale for Depression average, 3.6; range, 0-8). Three subjects had a greater than 50% decline in pain ratings by the completion of rTMS treatments, and 1 subject responded more slowly with greater than 50% improvement in pain by the end of the 3-month follow-up. An improvement in pain ratings was noted in responders within the first week. Conclusions: Although these are preliminary findings in an open treatment trial, the subjects in this trial are among the least likely to have a placebo response. Given that rTMS is a well-tolerated and noninvasive intervention, any sustained improvement in neuropathic pain with rTMS is encouraging.

Toward individualized post-electroconvulsive therapy care: Piloting the symptom-titrated, algorithm-based longitudinal ECT (STABLE) intervention

Objectives: Effective strategies to prolong remission after electroconvulsive therapy (ECT) are urgently needed. Fixed schedules for continuation ECT (C-ECT) cannot adapt to early signs of impending relapse. Symptom-Titrated, Algorithm-Based Longitudinal ECT (STABLE) is proposed as a novel patient-focused approach to individualize the ECT schedule. In STABLE, the ECT schedule adapts to symptom fluctuations to prevent overtreatment of those who do not need it and to recapture response in those who might have otherwise relapsed with a rigid dosing schedule. Here we back-test STABLE to optimize the algorithm for subsequent testing in a prospective trial. Methods: Three variations of the STABLE algorithm, differing in cutoff points to trigger or withhold additional ECT, were back-tested in a data set of 89 patients randomized to the C-ECT arm in the CORE (Consortium for Research on ECT) Study comparing C-ECT with combination pharmacotherapy. Results: The selected algorithm identified 100% of patients who ultimately relapsed as requiring additional ECT at an average of 2.2 weeks before relapse, while exposing 20% of sustained remitters to additional ECT. Other variations either failed to capture impending relapse or exposed an unacceptably large percentage of patients to potentially unnecessary ECT. Conclusions: This patient-focused approach to relapse prevention is an attempt to provide the first operationalized guidance to the field regarding how to conduct C-ECT. The effectiveness of this approach should be tested in a randomized controlled trial.

The emerging role for repetitive transcranial magnetic stimulation in optimizing the treatment of adolescent depression.

Major depressive disorder (MDD) in adolescents is a common illness and significant public health problem. Treatment is challenging because of recurrences and limited modalities. Selective serotonin reuptake inhibitors and cognitive behavioral therapy are considered the standard of care in severe or treatment-resistant MDD in this age group. However, responses to these interventions are often suboptimal. A growing body of research supports the efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of MDD in adults. Induced seizures are a primary safety concern, although this is rare with appropriate precautions. There is, however, limited experience with rTMS as a therapeutic intervention for adolescent psychiatric disturbances. This review will summarize the rTMS efficacy and safety data in adults and describe all published experience with adolescent MDD. Applications in other adolescent psychiatric illnesses such as schizophrenia and attention-deficit/hyperactivity disorder are reviewed. Safety and ethical issues are paramount with investigational treatments in adolescent psychiatric illnesses. However, further research with rTMS in adolescent MDD is imperative to establish standards for optimal stimulation site, treatment parameters, and its role in treatment algorithms. These may diverge from adult data. Early intervention with neuromodulation could also hold the promise of addressing the developmental course of dysfunctional neurocircuitry.